Efficacy and safety of biologics targeting interleukin-6, -12/23 and -17 pathways for peripheral psoriatic arthritis: a network meta-analysis

Efficacy and safety of biologics targeting interleukin-6, -12/23 and -17 pathways for peripheral... Abstract Objective To investigate the comparative efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors for patients with active PsA. Methods Randomized controlled trials evaluating the efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors were identified by a comprehensive systematic literature review. Pairwise meta-analyses and Bayesian network meta-analyses using the random effects model were performed to estimate pooled odds ratios (ORs) and 95% credible intervals of attaining a 20% or 50% improvement in ACR criteria (ACR20 and ACR50, respectively) across trials. Results Six trials were identified that included 2411 participants and 11 treatments. Pairwise meta-analysis showed that secukinumab, ustekinumab and ixekizumab demonstrated superior efficacy over placebo in achieving an ACR20 and ACR50 response. However, ixekizumab has a higher incidence of adverse events (AEs) than placebo. In contrast, ustekinumab has a higher tolerability (less likely to be discontinued due to AEs) than placebo. Network meta-analysis showed that secukinumab (300 mg monthly) had the highest efficacy in achieving ACR20 and ACR50, whereas clazakizumab (200 mg monthly), ustekinumab (45 mg 12 weekly) and secukinumab (150 mg monthly) had the lowest probability of having AEs, serious AEs and intolerability, respectively. Considering the overall risk–benefit profile, secukinumab (150 mg monthly) may offer an optimal balance for peripheral PsA patients. Conclusion Secukinumab may be the safest and most efficacious short-term treatment for peripheral PsA among all the new biologics targeting IL-6, IL-12/23 and IL-17 pathways. psoriatic arthritis, interleukin inhibitors, efficacy, safety, network meta-analysis Rheumatology key messages The comparative efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors in PsA were calculated. Explicit rankings of the optimal treatment for PsA based on efficacy, safety and tolerability were determined. Secukinumab may be the safest and most efficacious treatment targeting these pathways in PsA. Introduction PsA is a chronic inflammatory disease that affects both skin and joints [1]. It is a heterogeneous disease characterized by synovitis, enthesitis, dactylitis and spondylitis resulting in progressive bone and cartilage destruction and pathologic new bone formation, leading to impaired function and a reduced quality of life [2, 3]. Treatment of PsA has been revolutionized with the advent of anti-TNF therapies, which have been shown to be efficacious [4]. However, not all patients are responsive to anti-TNF treatment, highlighting the need for a better understanding of the cellular and molecular mechanisms that govern the disease. PsA associations with single nucleotide polymorphisms in IL-23 receptor (IL-23R) as well as TNF receptor-associated factor 3 interacting protein 2 (TRAF3IP2) and nuclear factor κB activator 1 (Act1), a molecule downstream of the IL-17 receptor (IL-17R), have linked the IL-23/IL-17 axis to disease pathology [5]. The differentiation of naïve CD4+ T cells into Th17 is induced by the combination of TGF-β and IL-6 via nuclear hormone receptor retinoic acid–related orphan receptor γt [6]. Clinically, the IL-12/23 antagonist ustekinumab and the IL-17 mAbs secukinumab and ixekizumab inhibit radiographic progression in patients with PsA who have peripheral joint involvement [7–11]. Clazakizumab, an mAb with high affinity and specificity for the IL-6 cytokine, has also demonstrated clinical efficacy in PsA [12]. As patients with PsA require lifelong treatment, reliable evidence of the comparative benefits and harms of these biologic therapies is needed to make informed clinical decisions regarding their use. Although head-to-head randomized trials are considered the gold standard of comparative evidence, they are not available for comparisons of all biologic treatments. Meta-analyses are conducted to assess the strength of recommendations and quality of evidence available for a disease and multiple treatment alternatives, improving the precision of estimates of effect and answering questions not posed by individual studies. In network meta-analyses, several treatments can be compared by connecting evidence from clinical trials that have investigated two or more treatments. The resulting trial network may allow estimation of the relative effects of all pairs of treatments, taking direct and indirect evidence into account, in order to provide a clinically useful comparative efficacy and safety summary that can guide clinical decisions [13–16]. The objective of this systematic review and network meta-analysis is to compare the efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors against placebo in the treatment of PsA. Methods Study selection and eligibility criteria This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension statement for network meta-analyses of health care intervention studies [17] and registered on the International Prospective Register of Systematic Reviews (PROSPERO) under the code CRD42016048166 (supplementary Table S1, available at Rheumatology online). Patients were defined as adults (⩾18 years of age) with a clinical diagnosis of PsA. The intervention was defined as randomized controlled trials (RCTs) investigating the efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors for PsA patients from January 2000. The search strategy included the key terms psoriatic arthritis, IL inhibitor, secukinumab, brodalumab, ustekinumab, clazakizumab ixekizumab and RCTs. The comparator was any biologic DMARD (bDMARD), synthetic DMARD (sDMARD), glucocorticoid, NSAID, combination of any of these or placebo. The outcomes were efficacy and safety. References from all retrieved publications were also searched manually for relevant studies. Studies meeting the following inclusion criteria were included: randomized, placebo-controlled trials comparing the efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors with placebo in patients with active PsA (defined as having at least three swollen and three tender joints), duration of study of at least 24 weeks and a 20% or 50% improvement in ACR criteria (ACR20 or ACR50, respectively) reported as the primary or major secondary outcome at week 24. The exclusion criteria were as follows: trials comparing different doses of the same medication only, trials of psoriasis without subgroup analysis of PsA patients, studies without a designated intervention/comparator arm, the presence of active inflammatory diseases other than PsA, trials where patients had concomitant use of TNF-α inhibitors (TNFis) and studies reported in a language other than English. The search was performed in PubMed, Embase, Web of Knowledge and ClinicalTrials.gov on 7 December 2016 without language restrictions. Details on the complete search strategy are provided in supplementary Table S2, available at Rheumatology online. Data extraction and evaluation of quality Treatment effects were evaluated based on efficacy (ACR20, ACR50) at week 24 and safety [any adverse event (AE), serious adverse event (SAE)] and tolerability (discontinuation due to AE) at week 16 or 24 as reported in the randomized trials (supplementary Table S3, available at Rheumatology online). The quality of the included studies was reviewed and assessed by two investigators (D.Z.W., J.Y.) independently using the Cochrane Collaboration’s tool for assessing the risk of bias. The quality of evidence across pooled studies (risk of bias, inconsistency, indirectness, imprecision and publication bias) was assessed by two researchers (D.Z.W., J.Y.) following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach using the online version of GRADEproGDT software (www.gradepro.org, McMaster University, 2016). Summary of Findings tables were created for every rated outcome following Cochrane-compliant rules. Disagreements were resolved first by discussion and then by consulting a third author for arbitration (L.S.T.). Statistical analysis Traditional meta-analyses were conducted on studies directly comparing all treatments of IL-6, IL-12/23 and IL-17 inhibitors with placebo and odd ratios (ORs) with corresponding 95% CIs were reported. To investigate the effect of prior TNFi exposure on the efficacy of ustekinumab and secukinumab, a subgroup analysis was performed. A random effects model (Dersimonian–Laird method) was used to estimate the summarized effect size, assuming that heterogeneity always exists. All statistical analysis in these meta-analyses was performed using RevMan 5.3 (Cochrane Collaboration, London, UK). A two-tailed P-value <0.05 was considered significant. In addition to the traditional meta-analyses, Bayesian network meta-analyses were performed to compare all treatments of IL-6, IL-12/23 and IL17 inhibitors and ORs with corresponding 95% credible interval (CrIs) were reported. This allows the comparison of all available treatments across trials and accounts for multiple comparisons in trials with more than two treatment groups [18]. The network was plotted using STATA (version 12.0; StataCorp, College Station, TX, USA). The network meta-analyses were performed with a random effects model based on a Bayesian framework using Markov chain Monte Carlo methods in WinBUGS (MRC Bio-statistics Unit, Cambridge, UK). The Excel-based Network Meta-Analysis Tool (Microsoft, Redmond, WA, USA) was used to simplify running and reporting the network meta-analyses [19]. An inconsistency plot was used to show the posterior mean deviance of the individual data points to identify any loops in the treatment network where inconsistency is present [20]. To facilitate interpretation of estimated treatment effects, we calculated several metrics for each intervention. A probabilistic analysis was performed to estimate the rank probabilities based on the network meta-analysis. The rank probabilities were summarized for each treatment in order to obtain the surface under the cumulative ranking curve (SUCRA) [21]. An intervention with a SUCRA value of 100 is certain to be the best, whereas an intervention with 0 is certain to be the worst. Pooled ORs from network meta-analyses and their corresponding ORs from traditional meta-analyses were compared to assess the consistency between direct and indirect evidence. Results Characteristics of included studies A total of 329 studies were retrieved. Six studies investigating secukinumab, ustekinumab, clazakizumab and ixekizumab were included in the analysis (supplementary Fig. S1, available at Rheumatology online) [7–9, 11, 12, 22]. Across all interventions, the mean age of patients ranged from 45 to 51 years, the percentage of female patients ranged from 43 to 60 and the follow-up period ranged from 24 to 52 weeks. In total, 2411 patients were included in our primary analysis of efficacy (ACR20, ACR50), safety (AEs, SAEs) and tolerability (discontinuation due to AEs) (supplementary Table S3, available at Rheumatology online). Ten interventions of secukinumab, ustekinumab, clazakizumab and ixekizumab were analysed in this study (supplementary Fig. S2, available at Rheumatology online). Risk of bias and quality of evidence The risk-of-bias assessment indicated that all included studies were of high quality (supplementary Fig. S3A and S3B, available at Rheumatology online.). All trials were judged to have a low risk of bias for randomization method, allocation concealment, blinding of participants and personnel, blinding of outcome assessment and incomplete outcome data (supplementary Fig. S3A, available at Rheumatology online). All six trials reported the use of last observation carried forward for imputation of missing data. All included trials received financial funding from a commercial body and stated a clear source of funding. Publication bias was assessed using funnel plots in terms of ACR20, ACR50, AEs, SAEs and tolerability (supplementary Fig. S4, available at Rheumatology online). When considering efficacy, safety and tolerability parameters, all trials were of generally high quality according to GRADEpro assessment except the quality of evidence of clazakizumab 25 mg monthly, which was moderate in terms of ACR20 and ACR50, and the quality of evidence of secukinumab 150 mg monthly, which was moderate in terms of tolerability (supplementary Table S4, available at Rheumatology online). Meta-analysis of direct treatment effects In traditional meta-analyses, we obtained direct evidence by comparing 10 interventions of IL-6, IL-12/23 and IL-17 inhibitors with placebo. Pooled effect sizes suggested that all biologics, irrespective of dose, improved ACR20 and ACR50 at week 24 when compared with placebo, except clazakizumab 200 mg monthly [ACR20: OR 1.23 (95% CI 0.50, 3.04); ACR50: OR 1.88 (95% CI 0.61, 5.78)] (supplementary Table S5 and Figs. S5A and S5B, available at Rheumatology online). There was no significant difference between secukinumab, clazakizumab and placebo in terms of AEs, SAEs and tolerability. Ixekizumab (both 80 mg every 2 weeks and 80 mg monthly) had more AEs than placebo, while ustekinumab (45 mg and 90 mg) was even more tolerable than placebo [OR 0.28 (95% CI 0.10, 0.78) and OR 0.32 (95% CI 0.13, 0.83), respectively] (supplementary Table S5 and Figs. S5C, S5D and S5E, available at Rheumatology online). ACR20 response according to prior anti-TNF exposure Two trials reported the effects of prior anti-TNF exposure on the efficacy of ustekinumab and secukinumab (supplementary Table S6, available at Rheumatology online). Anti-TNF-naïve patients responded significantly better than placebo patients, irrespective of dose. In contrast, only higher doses of secukinumab and ustekinumab were significantly more effective than placebo in achieving ACR20 in anti-TNF-failure patients. Inconsistency analysis We carried out comparisons among 10 interventions of the four inhibitors through network meta-analysis. ORs and corresponding 95% CrIs from network meta-analyses for ACR20, ACR50, AEs, SAEs and tolerability are presented in Figs. 1–3. Direct evidence from network meta-analysis was generally in compliance with traditional meta-analyses (supplementary Table S5, available at Rheumatology online). Fig. 1 View largeDownload slide Network meta-analysis of efficacy (ACR20 and ACR50) Treatments are reported in order of ACR20 ranking according to the SUCRA. Comparisons should be read from left to right. The efficacy estimate is located at the intersection of the column defining treatment and the row defining treatment. For ACR20, an OR > 1 favours the column defining treatment. For ACR50, an OR > 1 favours the row defining treatment. To obtain ORs for comparisons in the opposing direction, reciprocals should be taken. Fig. 1 View largeDownload slide Network meta-analysis of efficacy (ACR20 and ACR50) Treatments are reported in order of ACR20 ranking according to the SUCRA. Comparisons should be read from left to right. The efficacy estimate is located at the intersection of the column defining treatment and the row defining treatment. For ACR20, an OR > 1 favours the column defining treatment. For ACR50, an OR > 1 favours the row defining treatment. To obtain ORs for comparisons in the opposing direction, reciprocals should be taken. Fig. 2 View largeDownload slide Network meta-analysis of safety (AEs and SAEs) Treatments are reported in order of AE ranking according to SUCRAs. Comparisons should be read from left to right. The safety estimate is located at the intersection of the column defining treatment and the row defining treatment. For AEs, an OR > 1 favours the row defining treatment. For SAEs, an OR > 1 favours the column defining treatment. To obtain ORs for comparisons in the opposing direction, reciprocals should be taken. Fig. 2 View largeDownload slide Network meta-analysis of safety (AEs and SAEs) Treatments are reported in order of AE ranking according to SUCRAs. Comparisons should be read from left to right. The safety estimate is located at the intersection of the column defining treatment and the row defining treatment. For AEs, an OR > 1 favours the row defining treatment. For SAEs, an OR > 1 favours the column defining treatment. To obtain ORs for comparisons in the opposing direction, reciprocals should be taken. Fig. 3 View largeDownload slide Network meta-analysis of tolerability (discontinuation due to AEs) Treatments are reported in order of tolerability ranking according to SUCRAs. Comparisons should be read from left to right. The tolerability estimate is located at the intersection of the column defining treatment and the row defining treatment. For tolerability, an OR < 1 favours the column defining treatment. Fig. 3 View largeDownload slide Network meta-analysis of tolerability (discontinuation due to AEs) Treatments are reported in order of tolerability ranking according to SUCRAs. Comparisons should be read from left to right. The tolerability estimate is located at the intersection of the column defining treatment and the row defining treatment. For tolerability, an OR < 1 favours the column defining treatment. Network meta-analysis of direct comparisons All treatments of ustekinumab, secukinumab and ixekizumab showed significant differences when compared with placebo in both ACR20 and ACR50. Contrary to the findings of traditional meta-analyses (supplementary Table S5, available at Rheumatology online), clazakizumab 25 mg monthly was not superior to placebo in the network meta-analysis. All these inhibitors were comparable to placebo in terms of safety and tolerability except secukinumab 150 mg monthly, which was more tolerable than placebo [OR 0.23 (95% CrI 0.03, 0.83)] (Figs. 1–3). Network meta-analysis of mixed comparisons With regards to the ACR20 response for IL-6, IL-12/23 and IL-17 inhibitors, secukinumab 300 mg monthly was more effective than secukinumab 75 mg monthly [OR 1.97 (95% CrI 1.02, 3.56)], ustekinumab 45 mg every 12 weeks [OR 2.71 (95% CrI 1.20, 5.92)] and clazakizumab 200 mg monthly [OR 6.22 (95% CrI 1.77, 20.68)]. Secukinumab 150 mg monthly was more effective than ustekinumab 45 mg every 12 weeks [OR 1.89 (95% CrI 1.00, 3.62)] or clazakizumab 200 mg monthly [OR 4.28 (95% CrI 1.39, 14.29)]. Secukinumab 75 mg monthly was more effective than ustekinumab 45 mg every 12 weeks [OR 3.22 (95% CrI 1.04, 10.90)]. With regards to the ACR50 response of IL-6, IL-12/23 and IL-17 inhibitors, secukinumab 300 mg was more effective than ustekinumab 45 mg [OR 2.60 (95% CrI 1.06, 6.36)] (Fig. 1). Concerning the risk of having an AE with IL-6, IL-12/23 and IL-17 inhibitors, the risk was higher for ixekizumab 80 mg monthly when compared with secukinumab 75 mg monthly [OR 2.44 (95% CrI 1.24, 4.80)] and clazakizumab 200 mg monthly [OR 3.19 (95% CrI 1.01, 9.61)]. In addition, the risk of having an SAE for ixekizumab 80 mg monthly was also higher than for ustekinumab 90 mg every 12 weeks [OR 5.96 (95% CrI 1.14, 49.07)] (Fig. 2). With regards to tolerability, secukinumab 150 mg monthly and ustekinumab (45 mg and 90 mg every 12 weeks) were significantly less likely to be discontinued due to AEs than ixekizumab 80 mg every 2 weeks. Secukinumab (75 mg and 150 mg monthly), ustekinumab (45 mg and 90 mg every 12 weeks) and clazakizumab 25 mg monthly were statistically significantly less likely to be discontinued due to AEs than clazakizumab 200 mg monthly (Fig. 3). Ranking of treatments by efficacy, safety and tolerability The relative ranking of the 10 interventions based on their SUCRA are shown in Table 1, indicating the probability for each treatment to be the most effective, safe or tolerable (first-best) regimen. Secukinumab 300 mg monthly had the highest efficacy in achieving ACR20 and ACR50 responses. Clazakizumab 200 mg monthly, ustekinumab 45 mg every 12 weeks and secukinumab 150 mg monthly had the lowest probability of having AEs, SAEs and discontinuation due to AEs, respectively. On the other hand, ixekizumab 80 mg monthly had a higher probability of having AEs and SAEs, whereas tolerability was poorer in patients treated with clazakizumab 200 mg monthly (Table 1). Table 1 SUCRAs of treatments according to ACR20, ACR50, AEs, SAEs and tolerability Treatment  Efficacy  Safety  Tolerability, %  ACR20, %  ACR50, %  AEs, %  SAEs, %  Placebo  4.31  1.74  71.93  48.58  32.13  Ustekinumab 90 mg every 12 weeks  54.04  55.26  53.28  83.48  76.35  Ustekinumab 45 mg every 12 weeks  38.61  38.11  44.39  76.20  79.84  Secukinumab 300 mg monthly  96.42  91.64  60.81  30.29  45.73  Secukinumab 150 mg monthly  84.54  85.09  53.96  60.60  82.09  Secukinumab 75 mg monthly  62.93  59.15  80.19  64.09  54.13  Clazakizumab 200 mg monthly  9.42  19.70  87.44  26.86  8.64  Clazakizumab 100 mg monthly  42.19  45.31  31.36  58.83  47.91  Clazakizumab 25 mg monthly  42.28  40.05  39.62  47.81  66.28  Ixekizumab 80 mg every 2 weeks  64.43  66.11  14.95  36.39  14.96  Ixekizumab 80 mg monthly  50.84  47.84  12.08  16.87  41.93  Treatment  Efficacy  Safety  Tolerability, %  ACR20, %  ACR50, %  AEs, %  SAEs, %  Placebo  4.31  1.74  71.93  48.58  32.13  Ustekinumab 90 mg every 12 weeks  54.04  55.26  53.28  83.48  76.35  Ustekinumab 45 mg every 12 weeks  38.61  38.11  44.39  76.20  79.84  Secukinumab 300 mg monthly  96.42  91.64  60.81  30.29  45.73  Secukinumab 150 mg monthly  84.54  85.09  53.96  60.60  82.09  Secukinumab 75 mg monthly  62.93  59.15  80.19  64.09  54.13  Clazakizumab 200 mg monthly  9.42  19.70  87.44  26.86  8.64  Clazakizumab 100 mg monthly  42.19  45.31  31.36  58.83  47.91  Clazakizumab 25 mg monthly  42.28  40.05  39.62  47.81  66.28  Ixekizumab 80 mg every 2 weeks  64.43  66.11  14.95  36.39  14.96  Ixekizumab 80 mg monthly  50.84  47.84  12.08  16.87  41.93  The higher the SUCRA of efficacy, safety and tolerability, the more effective, safe and tolerable is each treatment. All interventions were ranked by their overall probability to be the best treatment after considering the efficacy (ACR20, ACR50), safety (AEs, SAEs) and tolerability (Fig. 4). Due to a lack of a dose response and clear evidence of efficacy for clazakizumab, this drug has not been ranked until further studies are available to confirm the appropriate dose. The top four ranked interventions were secukinumab 150 mg monthly, secukinumab 300 mg monthly, ustekinumab 90 mg every 12 weeks and secukinumab 75 mg monthly. Fig. 4 View largeDownload slide Ranking of treatments according to primary outcomes: efficacy, safety and tolerability The cumulative percentages after normalization (0–100) are shown in the key. Every drug was scored with points up to a maximum of 20 for ACR20, ACR50, AEs, SAEs and tolerability (overall maximum score 100), with data from rankograms and SUCRAs. Fig. 4 View largeDownload slide Ranking of treatments according to primary outcomes: efficacy, safety and tolerability The cumulative percentages after normalization (0–100) are shown in the key. Every drug was scored with points up to a maximum of 20 for ACR20, ACR50, AEs, SAEs and tolerability (overall maximum score 100), with data from rankograms and SUCRAs. Discussion Our meta-analysis aimed to answer a commonly encountered question in clinical practice: What would be the first biologic agent of choice for patients in whom TNFis may not be appropriate? Patients in whom TNFis may not be appropriate include, for example, patients with co-morbidities or those with a history of infections or patients who prefer not to be treated with a TNFi. This network meta-analysis represents the most comprehensive analysis of data for the currently available and upcoming inhibitors targeting the IL-6, IL-12/23 and IL-17 pathways for patients with PsA. Secukinumab and ixekizumab are recombinant, high-affinity, fully human IgG1κ and IgG4κ mAbs, respectively, that selectively bind and neutralize IL-17A [10, 23–25]. Ustekinumab is a human mAb that binds to the shared p40 subunit of IL-12 and IL-23, blocking signalling of their cognate receptors [26–28]. Clazakizumab is a monoclonal antibody with high affinity and specificity for IL-6 rather than IL-6 receptor [29]. Brodalumab, a human anti-IL-17RA mAb, was not included in the network meta-analysis due to safety concerns (increased risk of suicidal ideation and behaviour) [22, 30]. Apremilast was also not included in our network meta-analysis because of its moderate efficacy on joints, skin and entheses in PsA [31–33]. Indeed, the EULAR recommendation stated that apremilast may be considered in patients with peripheral arthritis and an inadequate response to at least one conventional synthetic DMARD, in whom bDMARDs are not appropriate [34]. In terms of efficacy, we demonstrated that secukinumab 300 mg monthly had the highest short-term efficacy in achieving ACR20 and ACR50. A previous meta-analysis also reported that secukinumab at doses of 150 mg and 300 mg monthly were more likely to achieve an ACR20 response at weeks 12 and 24 compared with those who received ustekinumab, even though the difference did not reach statistical significance between secukinumab 150/300 mg and ustekinumab 90 mg [35]. In contrast to that study, we also looked at safety and tolerability and reported that clazakizumab 200 mg monthly, ustekinumab 45 mg every 12 weeks and secukinumab 150 mg monthly were least likely to have AEs, SAEs and discontinuation due to AEs, respectively. This study provided new evidence that secukinumab 150 mg monthly may provide the optimal treatment among the IL-6, IL-12/23 and IL-17 inhibitors. If there is no clear evidence of efficacy, the overall probability is unhelpful to take further due to the high weight of safety and tolerability. Together with comments from reviewers, we therefore excluded different dosages of clazakizumab from the overall probability ranking. With regards to clazakizumab, the ACR20 response rates at week 24 in all tested dosages of clazakizumab were numerically higher than placebo, but the differences between high-dose clazakizumab (200 mg) and placebo was not statistically significant. High-dose clazakizumab (200 mg) was not superior to the lower doses (25 mg or 100 mg) in achieving ACR20. The main reason for the absence of dose response was possibly due to saturation of IL-6 binding and neutralization at the lowest dose tested (25 mg) [12]. Network meta-analysis also showed overall inferior performance of clazakizumab 200 mg than the lower doses. This could have been due to the negative effects of patient-reported outcomes secondary to lower tolerability at the 200 mg dose, as displayed by a higher frequency of AEs and more discontinuations in this group. To our knowledge, this network meta-analysis is the first to address comparative efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors with explicit rankings of ACR20, ACR50, AEs, SAEs and tolerability. This indirect comparison technique allows us to compare various pairs of biologic agents for which direct comparison data are not available. We also exclusively included only RCTs, which are considered the most valid study design to prove the efficacy of an intervention. Thus the primary data included in these analyses were of high quality. This network meta-analysis was standardized by the Preferred Reporting Items for Systematic Reviews and Meta-analyses principle to minimize errors and ensure the validity of findings. Although pooled estimates had a certain degree of heterogeneity, the random effects model approach took variations into account at the study level. Nevertheless, our results should be interpreted with caution due to several limitations in this study. First, the number of trials included in this study was relatively small. In fact, there was only one study for clazakizumab and ixekizumab. Thus the indirect comparison between secukinumab and ustekinumab and clazakizumab and ixekizumab relied on just one clinical trial. This might affect the robustness of the comparison, as the estimated effect of clazakizumab and ixekizumab might be less accurate. We acknowledge the fact that results from this study may not be strong enough to serve as a clinical guide. Nonetheless, we believe data from this study will help clinicians put the available efficacy and safety data into perspective. Second, all included primary studies were funded by pharmaceutical companies, which could raise a concern over their influence on the results. Recent studies have demonstrated that industry-supported trials tend to show more favourable results to their products compared with trials that are not supported by the industry [36, 37]. Third, outcome measurements such as the ACR20 and ACR50 are not specifically designed for PsA [38]. As a result, this outcome definition does not capture the response of other disease manifestations, including axial disease, enthesitis, dactylitis, uveitis and skin and nail psoriasis [39]. Given that different disease manifestations are likely to have different responses to these drugs, the choice of treatment should be individualized based on the current clinical manifestations of the disease according to the recommendations of the 2017 task force [40]. For instance, one should consider secukinumab 300 mg monthly (licensed dosage for psoriasis) for PsA patients with coexistent moderate to severe psoriasis to achieve better skin and joint response, although secukinumab 150 mg monthly had the lower probability of having AEs, SAEs and discontinuation due to AEs. Fourth, we conducted these comparisons for a very specific clinical situation. Our results are not applicable to other clinical settings, such as those who are naive to DMARDs or TNFi. Our outcome of interest was the ACR20 and ACR50 response rate at week 24, AEs and SAEs at weeks 12 and 24, which also could not be extrapolated to other durations or to different outcomes such as the radiographic progression. Finally, differences in baseline characteristics may account for some of the differences in response to biologics versus placebo across different trials [41]. Conclusions In conclusion, secukinumab may be the safest and most efficacious short-term treatment for peripheral PsA among all the new biologics targeting the IL-6, IL-12/23 and IL-17 pathways. Acknowledgements L.S.T. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. D.Z.W., J.Y. and L.S.T. conceived and designed the experiments. J.Y. and D.Z.W. performed the experiments. D.Z.W. and J.Y. analysed the data. D.Z.W., J.Y. and L.S.T. contributed materials and analysis tools. D.Z.W., J.Y. and L.S.T. wrote the paper. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. References 1 Ritchlin CT, Colbert RA, Gladman DD. Psoriatic arthritis. 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Ann Rheum Dis  2017;0:1–15. 41 Druyts E, Palmer JB, Balijepalli C et al.   Treatment modifying factors of biologics for psoriatic arthritis: a systematic review and Bayesian meta-regression. Clin Exp Rheumatol  2017; 35: 681– 8. Google Scholar PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Efficacy and safety of biologics targeting interleukin-6, -12/23 and -17 pathways for peripheral psoriatic arthritis: a network meta-analysis

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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1462-0324
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1462-0332
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10.1093/rheumatology/kex452
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Abstract

Abstract Objective To investigate the comparative efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors for patients with active PsA. Methods Randomized controlled trials evaluating the efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors were identified by a comprehensive systematic literature review. Pairwise meta-analyses and Bayesian network meta-analyses using the random effects model were performed to estimate pooled odds ratios (ORs) and 95% credible intervals of attaining a 20% or 50% improvement in ACR criteria (ACR20 and ACR50, respectively) across trials. Results Six trials were identified that included 2411 participants and 11 treatments. Pairwise meta-analysis showed that secukinumab, ustekinumab and ixekizumab demonstrated superior efficacy over placebo in achieving an ACR20 and ACR50 response. However, ixekizumab has a higher incidence of adverse events (AEs) than placebo. In contrast, ustekinumab has a higher tolerability (less likely to be discontinued due to AEs) than placebo. Network meta-analysis showed that secukinumab (300 mg monthly) had the highest efficacy in achieving ACR20 and ACR50, whereas clazakizumab (200 mg monthly), ustekinumab (45 mg 12 weekly) and secukinumab (150 mg monthly) had the lowest probability of having AEs, serious AEs and intolerability, respectively. Considering the overall risk–benefit profile, secukinumab (150 mg monthly) may offer an optimal balance for peripheral PsA patients. Conclusion Secukinumab may be the safest and most efficacious short-term treatment for peripheral PsA among all the new biologics targeting IL-6, IL-12/23 and IL-17 pathways. psoriatic arthritis, interleukin inhibitors, efficacy, safety, network meta-analysis Rheumatology key messages The comparative efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors in PsA were calculated. Explicit rankings of the optimal treatment for PsA based on efficacy, safety and tolerability were determined. Secukinumab may be the safest and most efficacious treatment targeting these pathways in PsA. Introduction PsA is a chronic inflammatory disease that affects both skin and joints [1]. It is a heterogeneous disease characterized by synovitis, enthesitis, dactylitis and spondylitis resulting in progressive bone and cartilage destruction and pathologic new bone formation, leading to impaired function and a reduced quality of life [2, 3]. Treatment of PsA has been revolutionized with the advent of anti-TNF therapies, which have been shown to be efficacious [4]. However, not all patients are responsive to anti-TNF treatment, highlighting the need for a better understanding of the cellular and molecular mechanisms that govern the disease. PsA associations with single nucleotide polymorphisms in IL-23 receptor (IL-23R) as well as TNF receptor-associated factor 3 interacting protein 2 (TRAF3IP2) and nuclear factor κB activator 1 (Act1), a molecule downstream of the IL-17 receptor (IL-17R), have linked the IL-23/IL-17 axis to disease pathology [5]. The differentiation of naïve CD4+ T cells into Th17 is induced by the combination of TGF-β and IL-6 via nuclear hormone receptor retinoic acid–related orphan receptor γt [6]. Clinically, the IL-12/23 antagonist ustekinumab and the IL-17 mAbs secukinumab and ixekizumab inhibit radiographic progression in patients with PsA who have peripheral joint involvement [7–11]. Clazakizumab, an mAb with high affinity and specificity for the IL-6 cytokine, has also demonstrated clinical efficacy in PsA [12]. As patients with PsA require lifelong treatment, reliable evidence of the comparative benefits and harms of these biologic therapies is needed to make informed clinical decisions regarding their use. Although head-to-head randomized trials are considered the gold standard of comparative evidence, they are not available for comparisons of all biologic treatments. Meta-analyses are conducted to assess the strength of recommendations and quality of evidence available for a disease and multiple treatment alternatives, improving the precision of estimates of effect and answering questions not posed by individual studies. In network meta-analyses, several treatments can be compared by connecting evidence from clinical trials that have investigated two or more treatments. The resulting trial network may allow estimation of the relative effects of all pairs of treatments, taking direct and indirect evidence into account, in order to provide a clinically useful comparative efficacy and safety summary that can guide clinical decisions [13–16]. The objective of this systematic review and network meta-analysis is to compare the efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors against placebo in the treatment of PsA. Methods Study selection and eligibility criteria This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension statement for network meta-analyses of health care intervention studies [17] and registered on the International Prospective Register of Systematic Reviews (PROSPERO) under the code CRD42016048166 (supplementary Table S1, available at Rheumatology online). Patients were defined as adults (⩾18 years of age) with a clinical diagnosis of PsA. The intervention was defined as randomized controlled trials (RCTs) investigating the efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors for PsA patients from January 2000. The search strategy included the key terms psoriatic arthritis, IL inhibitor, secukinumab, brodalumab, ustekinumab, clazakizumab ixekizumab and RCTs. The comparator was any biologic DMARD (bDMARD), synthetic DMARD (sDMARD), glucocorticoid, NSAID, combination of any of these or placebo. The outcomes were efficacy and safety. References from all retrieved publications were also searched manually for relevant studies. Studies meeting the following inclusion criteria were included: randomized, placebo-controlled trials comparing the efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors with placebo in patients with active PsA (defined as having at least three swollen and three tender joints), duration of study of at least 24 weeks and a 20% or 50% improvement in ACR criteria (ACR20 or ACR50, respectively) reported as the primary or major secondary outcome at week 24. The exclusion criteria were as follows: trials comparing different doses of the same medication only, trials of psoriasis without subgroup analysis of PsA patients, studies without a designated intervention/comparator arm, the presence of active inflammatory diseases other than PsA, trials where patients had concomitant use of TNF-α inhibitors (TNFis) and studies reported in a language other than English. The search was performed in PubMed, Embase, Web of Knowledge and ClinicalTrials.gov on 7 December 2016 without language restrictions. Details on the complete search strategy are provided in supplementary Table S2, available at Rheumatology online. Data extraction and evaluation of quality Treatment effects were evaluated based on efficacy (ACR20, ACR50) at week 24 and safety [any adverse event (AE), serious adverse event (SAE)] and tolerability (discontinuation due to AE) at week 16 or 24 as reported in the randomized trials (supplementary Table S3, available at Rheumatology online). The quality of the included studies was reviewed and assessed by two investigators (D.Z.W., J.Y.) independently using the Cochrane Collaboration’s tool for assessing the risk of bias. The quality of evidence across pooled studies (risk of bias, inconsistency, indirectness, imprecision and publication bias) was assessed by two researchers (D.Z.W., J.Y.) following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach using the online version of GRADEproGDT software (www.gradepro.org, McMaster University, 2016). Summary of Findings tables were created for every rated outcome following Cochrane-compliant rules. Disagreements were resolved first by discussion and then by consulting a third author for arbitration (L.S.T.). Statistical analysis Traditional meta-analyses were conducted on studies directly comparing all treatments of IL-6, IL-12/23 and IL-17 inhibitors with placebo and odd ratios (ORs) with corresponding 95% CIs were reported. To investigate the effect of prior TNFi exposure on the efficacy of ustekinumab and secukinumab, a subgroup analysis was performed. A random effects model (Dersimonian–Laird method) was used to estimate the summarized effect size, assuming that heterogeneity always exists. All statistical analysis in these meta-analyses was performed using RevMan 5.3 (Cochrane Collaboration, London, UK). A two-tailed P-value <0.05 was considered significant. In addition to the traditional meta-analyses, Bayesian network meta-analyses were performed to compare all treatments of IL-6, IL-12/23 and IL17 inhibitors and ORs with corresponding 95% credible interval (CrIs) were reported. This allows the comparison of all available treatments across trials and accounts for multiple comparisons in trials with more than two treatment groups [18]. The network was plotted using STATA (version 12.0; StataCorp, College Station, TX, USA). The network meta-analyses were performed with a random effects model based on a Bayesian framework using Markov chain Monte Carlo methods in WinBUGS (MRC Bio-statistics Unit, Cambridge, UK). The Excel-based Network Meta-Analysis Tool (Microsoft, Redmond, WA, USA) was used to simplify running and reporting the network meta-analyses [19]. An inconsistency plot was used to show the posterior mean deviance of the individual data points to identify any loops in the treatment network where inconsistency is present [20]. To facilitate interpretation of estimated treatment effects, we calculated several metrics for each intervention. A probabilistic analysis was performed to estimate the rank probabilities based on the network meta-analysis. The rank probabilities were summarized for each treatment in order to obtain the surface under the cumulative ranking curve (SUCRA) [21]. An intervention with a SUCRA value of 100 is certain to be the best, whereas an intervention with 0 is certain to be the worst. Pooled ORs from network meta-analyses and their corresponding ORs from traditional meta-analyses were compared to assess the consistency between direct and indirect evidence. Results Characteristics of included studies A total of 329 studies were retrieved. Six studies investigating secukinumab, ustekinumab, clazakizumab and ixekizumab were included in the analysis (supplementary Fig. S1, available at Rheumatology online) [7–9, 11, 12, 22]. Across all interventions, the mean age of patients ranged from 45 to 51 years, the percentage of female patients ranged from 43 to 60 and the follow-up period ranged from 24 to 52 weeks. In total, 2411 patients were included in our primary analysis of efficacy (ACR20, ACR50), safety (AEs, SAEs) and tolerability (discontinuation due to AEs) (supplementary Table S3, available at Rheumatology online). Ten interventions of secukinumab, ustekinumab, clazakizumab and ixekizumab were analysed in this study (supplementary Fig. S2, available at Rheumatology online). Risk of bias and quality of evidence The risk-of-bias assessment indicated that all included studies were of high quality (supplementary Fig. S3A and S3B, available at Rheumatology online.). All trials were judged to have a low risk of bias for randomization method, allocation concealment, blinding of participants and personnel, blinding of outcome assessment and incomplete outcome data (supplementary Fig. S3A, available at Rheumatology online). All six trials reported the use of last observation carried forward for imputation of missing data. All included trials received financial funding from a commercial body and stated a clear source of funding. Publication bias was assessed using funnel plots in terms of ACR20, ACR50, AEs, SAEs and tolerability (supplementary Fig. S4, available at Rheumatology online). When considering efficacy, safety and tolerability parameters, all trials were of generally high quality according to GRADEpro assessment except the quality of evidence of clazakizumab 25 mg monthly, which was moderate in terms of ACR20 and ACR50, and the quality of evidence of secukinumab 150 mg monthly, which was moderate in terms of tolerability (supplementary Table S4, available at Rheumatology online). Meta-analysis of direct treatment effects In traditional meta-analyses, we obtained direct evidence by comparing 10 interventions of IL-6, IL-12/23 and IL-17 inhibitors with placebo. Pooled effect sizes suggested that all biologics, irrespective of dose, improved ACR20 and ACR50 at week 24 when compared with placebo, except clazakizumab 200 mg monthly [ACR20: OR 1.23 (95% CI 0.50, 3.04); ACR50: OR 1.88 (95% CI 0.61, 5.78)] (supplementary Table S5 and Figs. S5A and S5B, available at Rheumatology online). There was no significant difference between secukinumab, clazakizumab and placebo in terms of AEs, SAEs and tolerability. Ixekizumab (both 80 mg every 2 weeks and 80 mg monthly) had more AEs than placebo, while ustekinumab (45 mg and 90 mg) was even more tolerable than placebo [OR 0.28 (95% CI 0.10, 0.78) and OR 0.32 (95% CI 0.13, 0.83), respectively] (supplementary Table S5 and Figs. S5C, S5D and S5E, available at Rheumatology online). ACR20 response according to prior anti-TNF exposure Two trials reported the effects of prior anti-TNF exposure on the efficacy of ustekinumab and secukinumab (supplementary Table S6, available at Rheumatology online). Anti-TNF-naïve patients responded significantly better than placebo patients, irrespective of dose. In contrast, only higher doses of secukinumab and ustekinumab were significantly more effective than placebo in achieving ACR20 in anti-TNF-failure patients. Inconsistency analysis We carried out comparisons among 10 interventions of the four inhibitors through network meta-analysis. ORs and corresponding 95% CrIs from network meta-analyses for ACR20, ACR50, AEs, SAEs and tolerability are presented in Figs. 1–3. Direct evidence from network meta-analysis was generally in compliance with traditional meta-analyses (supplementary Table S5, available at Rheumatology online). Fig. 1 View largeDownload slide Network meta-analysis of efficacy (ACR20 and ACR50) Treatments are reported in order of ACR20 ranking according to the SUCRA. Comparisons should be read from left to right. The efficacy estimate is located at the intersection of the column defining treatment and the row defining treatment. For ACR20, an OR > 1 favours the column defining treatment. For ACR50, an OR > 1 favours the row defining treatment. To obtain ORs for comparisons in the opposing direction, reciprocals should be taken. Fig. 1 View largeDownload slide Network meta-analysis of efficacy (ACR20 and ACR50) Treatments are reported in order of ACR20 ranking according to the SUCRA. Comparisons should be read from left to right. The efficacy estimate is located at the intersection of the column defining treatment and the row defining treatment. For ACR20, an OR > 1 favours the column defining treatment. For ACR50, an OR > 1 favours the row defining treatment. To obtain ORs for comparisons in the opposing direction, reciprocals should be taken. Fig. 2 View largeDownload slide Network meta-analysis of safety (AEs and SAEs) Treatments are reported in order of AE ranking according to SUCRAs. Comparisons should be read from left to right. The safety estimate is located at the intersection of the column defining treatment and the row defining treatment. For AEs, an OR > 1 favours the row defining treatment. For SAEs, an OR > 1 favours the column defining treatment. To obtain ORs for comparisons in the opposing direction, reciprocals should be taken. Fig. 2 View largeDownload slide Network meta-analysis of safety (AEs and SAEs) Treatments are reported in order of AE ranking according to SUCRAs. Comparisons should be read from left to right. The safety estimate is located at the intersection of the column defining treatment and the row defining treatment. For AEs, an OR > 1 favours the row defining treatment. For SAEs, an OR > 1 favours the column defining treatment. To obtain ORs for comparisons in the opposing direction, reciprocals should be taken. Fig. 3 View largeDownload slide Network meta-analysis of tolerability (discontinuation due to AEs) Treatments are reported in order of tolerability ranking according to SUCRAs. Comparisons should be read from left to right. The tolerability estimate is located at the intersection of the column defining treatment and the row defining treatment. For tolerability, an OR < 1 favours the column defining treatment. Fig. 3 View largeDownload slide Network meta-analysis of tolerability (discontinuation due to AEs) Treatments are reported in order of tolerability ranking according to SUCRAs. Comparisons should be read from left to right. The tolerability estimate is located at the intersection of the column defining treatment and the row defining treatment. For tolerability, an OR < 1 favours the column defining treatment. Network meta-analysis of direct comparisons All treatments of ustekinumab, secukinumab and ixekizumab showed significant differences when compared with placebo in both ACR20 and ACR50. Contrary to the findings of traditional meta-analyses (supplementary Table S5, available at Rheumatology online), clazakizumab 25 mg monthly was not superior to placebo in the network meta-analysis. All these inhibitors were comparable to placebo in terms of safety and tolerability except secukinumab 150 mg monthly, which was more tolerable than placebo [OR 0.23 (95% CrI 0.03, 0.83)] (Figs. 1–3). Network meta-analysis of mixed comparisons With regards to the ACR20 response for IL-6, IL-12/23 and IL-17 inhibitors, secukinumab 300 mg monthly was more effective than secukinumab 75 mg monthly [OR 1.97 (95% CrI 1.02, 3.56)], ustekinumab 45 mg every 12 weeks [OR 2.71 (95% CrI 1.20, 5.92)] and clazakizumab 200 mg monthly [OR 6.22 (95% CrI 1.77, 20.68)]. Secukinumab 150 mg monthly was more effective than ustekinumab 45 mg every 12 weeks [OR 1.89 (95% CrI 1.00, 3.62)] or clazakizumab 200 mg monthly [OR 4.28 (95% CrI 1.39, 14.29)]. Secukinumab 75 mg monthly was more effective than ustekinumab 45 mg every 12 weeks [OR 3.22 (95% CrI 1.04, 10.90)]. With regards to the ACR50 response of IL-6, IL-12/23 and IL-17 inhibitors, secukinumab 300 mg was more effective than ustekinumab 45 mg [OR 2.60 (95% CrI 1.06, 6.36)] (Fig. 1). Concerning the risk of having an AE with IL-6, IL-12/23 and IL-17 inhibitors, the risk was higher for ixekizumab 80 mg monthly when compared with secukinumab 75 mg monthly [OR 2.44 (95% CrI 1.24, 4.80)] and clazakizumab 200 mg monthly [OR 3.19 (95% CrI 1.01, 9.61)]. In addition, the risk of having an SAE for ixekizumab 80 mg monthly was also higher than for ustekinumab 90 mg every 12 weeks [OR 5.96 (95% CrI 1.14, 49.07)] (Fig. 2). With regards to tolerability, secukinumab 150 mg monthly and ustekinumab (45 mg and 90 mg every 12 weeks) were significantly less likely to be discontinued due to AEs than ixekizumab 80 mg every 2 weeks. Secukinumab (75 mg and 150 mg monthly), ustekinumab (45 mg and 90 mg every 12 weeks) and clazakizumab 25 mg monthly were statistically significantly less likely to be discontinued due to AEs than clazakizumab 200 mg monthly (Fig. 3). Ranking of treatments by efficacy, safety and tolerability The relative ranking of the 10 interventions based on their SUCRA are shown in Table 1, indicating the probability for each treatment to be the most effective, safe or tolerable (first-best) regimen. Secukinumab 300 mg monthly had the highest efficacy in achieving ACR20 and ACR50 responses. Clazakizumab 200 mg monthly, ustekinumab 45 mg every 12 weeks and secukinumab 150 mg monthly had the lowest probability of having AEs, SAEs and discontinuation due to AEs, respectively. On the other hand, ixekizumab 80 mg monthly had a higher probability of having AEs and SAEs, whereas tolerability was poorer in patients treated with clazakizumab 200 mg monthly (Table 1). Table 1 SUCRAs of treatments according to ACR20, ACR50, AEs, SAEs and tolerability Treatment  Efficacy  Safety  Tolerability, %  ACR20, %  ACR50, %  AEs, %  SAEs, %  Placebo  4.31  1.74  71.93  48.58  32.13  Ustekinumab 90 mg every 12 weeks  54.04  55.26  53.28  83.48  76.35  Ustekinumab 45 mg every 12 weeks  38.61  38.11  44.39  76.20  79.84  Secukinumab 300 mg monthly  96.42  91.64  60.81  30.29  45.73  Secukinumab 150 mg monthly  84.54  85.09  53.96  60.60  82.09  Secukinumab 75 mg monthly  62.93  59.15  80.19  64.09  54.13  Clazakizumab 200 mg monthly  9.42  19.70  87.44  26.86  8.64  Clazakizumab 100 mg monthly  42.19  45.31  31.36  58.83  47.91  Clazakizumab 25 mg monthly  42.28  40.05  39.62  47.81  66.28  Ixekizumab 80 mg every 2 weeks  64.43  66.11  14.95  36.39  14.96  Ixekizumab 80 mg monthly  50.84  47.84  12.08  16.87  41.93  Treatment  Efficacy  Safety  Tolerability, %  ACR20, %  ACR50, %  AEs, %  SAEs, %  Placebo  4.31  1.74  71.93  48.58  32.13  Ustekinumab 90 mg every 12 weeks  54.04  55.26  53.28  83.48  76.35  Ustekinumab 45 mg every 12 weeks  38.61  38.11  44.39  76.20  79.84  Secukinumab 300 mg monthly  96.42  91.64  60.81  30.29  45.73  Secukinumab 150 mg monthly  84.54  85.09  53.96  60.60  82.09  Secukinumab 75 mg monthly  62.93  59.15  80.19  64.09  54.13  Clazakizumab 200 mg monthly  9.42  19.70  87.44  26.86  8.64  Clazakizumab 100 mg monthly  42.19  45.31  31.36  58.83  47.91  Clazakizumab 25 mg monthly  42.28  40.05  39.62  47.81  66.28  Ixekizumab 80 mg every 2 weeks  64.43  66.11  14.95  36.39  14.96  Ixekizumab 80 mg monthly  50.84  47.84  12.08  16.87  41.93  The higher the SUCRA of efficacy, safety and tolerability, the more effective, safe and tolerable is each treatment. All interventions were ranked by their overall probability to be the best treatment after considering the efficacy (ACR20, ACR50), safety (AEs, SAEs) and tolerability (Fig. 4). Due to a lack of a dose response and clear evidence of efficacy for clazakizumab, this drug has not been ranked until further studies are available to confirm the appropriate dose. The top four ranked interventions were secukinumab 150 mg monthly, secukinumab 300 mg monthly, ustekinumab 90 mg every 12 weeks and secukinumab 75 mg monthly. Fig. 4 View largeDownload slide Ranking of treatments according to primary outcomes: efficacy, safety and tolerability The cumulative percentages after normalization (0–100) are shown in the key. Every drug was scored with points up to a maximum of 20 for ACR20, ACR50, AEs, SAEs and tolerability (overall maximum score 100), with data from rankograms and SUCRAs. Fig. 4 View largeDownload slide Ranking of treatments according to primary outcomes: efficacy, safety and tolerability The cumulative percentages after normalization (0–100) are shown in the key. Every drug was scored with points up to a maximum of 20 for ACR20, ACR50, AEs, SAEs and tolerability (overall maximum score 100), with data from rankograms and SUCRAs. Discussion Our meta-analysis aimed to answer a commonly encountered question in clinical practice: What would be the first biologic agent of choice for patients in whom TNFis may not be appropriate? Patients in whom TNFis may not be appropriate include, for example, patients with co-morbidities or those with a history of infections or patients who prefer not to be treated with a TNFi. This network meta-analysis represents the most comprehensive analysis of data for the currently available and upcoming inhibitors targeting the IL-6, IL-12/23 and IL-17 pathways for patients with PsA. Secukinumab and ixekizumab are recombinant, high-affinity, fully human IgG1κ and IgG4κ mAbs, respectively, that selectively bind and neutralize IL-17A [10, 23–25]. Ustekinumab is a human mAb that binds to the shared p40 subunit of IL-12 and IL-23, blocking signalling of their cognate receptors [26–28]. Clazakizumab is a monoclonal antibody with high affinity and specificity for IL-6 rather than IL-6 receptor [29]. Brodalumab, a human anti-IL-17RA mAb, was not included in the network meta-analysis due to safety concerns (increased risk of suicidal ideation and behaviour) [22, 30]. Apremilast was also not included in our network meta-analysis because of its moderate efficacy on joints, skin and entheses in PsA [31–33]. Indeed, the EULAR recommendation stated that apremilast may be considered in patients with peripheral arthritis and an inadequate response to at least one conventional synthetic DMARD, in whom bDMARDs are not appropriate [34]. In terms of efficacy, we demonstrated that secukinumab 300 mg monthly had the highest short-term efficacy in achieving ACR20 and ACR50. A previous meta-analysis also reported that secukinumab at doses of 150 mg and 300 mg monthly were more likely to achieve an ACR20 response at weeks 12 and 24 compared with those who received ustekinumab, even though the difference did not reach statistical significance between secukinumab 150/300 mg and ustekinumab 90 mg [35]. In contrast to that study, we also looked at safety and tolerability and reported that clazakizumab 200 mg monthly, ustekinumab 45 mg every 12 weeks and secukinumab 150 mg monthly were least likely to have AEs, SAEs and discontinuation due to AEs, respectively. This study provided new evidence that secukinumab 150 mg monthly may provide the optimal treatment among the IL-6, IL-12/23 and IL-17 inhibitors. If there is no clear evidence of efficacy, the overall probability is unhelpful to take further due to the high weight of safety and tolerability. Together with comments from reviewers, we therefore excluded different dosages of clazakizumab from the overall probability ranking. With regards to clazakizumab, the ACR20 response rates at week 24 in all tested dosages of clazakizumab were numerically higher than placebo, but the differences between high-dose clazakizumab (200 mg) and placebo was not statistically significant. High-dose clazakizumab (200 mg) was not superior to the lower doses (25 mg or 100 mg) in achieving ACR20. The main reason for the absence of dose response was possibly due to saturation of IL-6 binding and neutralization at the lowest dose tested (25 mg) [12]. Network meta-analysis also showed overall inferior performance of clazakizumab 200 mg than the lower doses. This could have been due to the negative effects of patient-reported outcomes secondary to lower tolerability at the 200 mg dose, as displayed by a higher frequency of AEs and more discontinuations in this group. To our knowledge, this network meta-analysis is the first to address comparative efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors with explicit rankings of ACR20, ACR50, AEs, SAEs and tolerability. This indirect comparison technique allows us to compare various pairs of biologic agents for which direct comparison data are not available. We also exclusively included only RCTs, which are considered the most valid study design to prove the efficacy of an intervention. Thus the primary data included in these analyses were of high quality. This network meta-analysis was standardized by the Preferred Reporting Items for Systematic Reviews and Meta-analyses principle to minimize errors and ensure the validity of findings. Although pooled estimates had a certain degree of heterogeneity, the random effects model approach took variations into account at the study level. Nevertheless, our results should be interpreted with caution due to several limitations in this study. First, the number of trials included in this study was relatively small. In fact, there was only one study for clazakizumab and ixekizumab. Thus the indirect comparison between secukinumab and ustekinumab and clazakizumab and ixekizumab relied on just one clinical trial. This might affect the robustness of the comparison, as the estimated effect of clazakizumab and ixekizumab might be less accurate. We acknowledge the fact that results from this study may not be strong enough to serve as a clinical guide. Nonetheless, we believe data from this study will help clinicians put the available efficacy and safety data into perspective. Second, all included primary studies were funded by pharmaceutical companies, which could raise a concern over their influence on the results. Recent studies have demonstrated that industry-supported trials tend to show more favourable results to their products compared with trials that are not supported by the industry [36, 37]. Third, outcome measurements such as the ACR20 and ACR50 are not specifically designed for PsA [38]. As a result, this outcome definition does not capture the response of other disease manifestations, including axial disease, enthesitis, dactylitis, uveitis and skin and nail psoriasis [39]. Given that different disease manifestations are likely to have different responses to these drugs, the choice of treatment should be individualized based on the current clinical manifestations of the disease according to the recommendations of the 2017 task force [40]. For instance, one should consider secukinumab 300 mg monthly (licensed dosage for psoriasis) for PsA patients with coexistent moderate to severe psoriasis to achieve better skin and joint response, although secukinumab 150 mg monthly had the lower probability of having AEs, SAEs and discontinuation due to AEs. Fourth, we conducted these comparisons for a very specific clinical situation. Our results are not applicable to other clinical settings, such as those who are naive to DMARDs or TNFi. Our outcome of interest was the ACR20 and ACR50 response rate at week 24, AEs and SAEs at weeks 12 and 24, which also could not be extrapolated to other durations or to different outcomes such as the radiographic progression. Finally, differences in baseline characteristics may account for some of the differences in response to biologics versus placebo across different trials [41]. Conclusions In conclusion, secukinumab may be the safest and most efficacious short-term treatment for peripheral PsA among all the new biologics targeting the IL-6, IL-12/23 and IL-17 pathways. Acknowledgements L.S.T. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. D.Z.W., J.Y. and L.S.T. conceived and designed the experiments. J.Y. and D.Z.W. performed the experiments. D.Z.W. and J.Y. analysed the data. D.Z.W., J.Y. and L.S.T. contributed materials and analysis tools. D.Z.W., J.Y. and L.S.T. wrote the paper. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. References 1 Ritchlin CT, Colbert RA, Gladman DD. Psoriatic arthritis. 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RheumatologyOxford University Press

Published: Mar 1, 2018

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